Submission For The Record of U.S. Department of Defense
Chairman Coffman, Ranking Member Kirkpatrick, distinguished Members of the Subcommittee; I thank you for the opportunity to provide this testimony on behalf of the Department of Defense (DoD) Gulf War Illness Research Program. This program studies the multi-symptom cluster known as Gulf War Illness (GWI) that afflicts as many as 250,000 of the 750,000 service members and Veterans who served in the Persian Gulf War theatre of operations during 1990 and 1991.
Overview of DoD GWI Research Funding
DoD-funded GWI research began in 1994 with the establishment of a Gulf War Veterans’ Illnesses Research Program (GWVIRP) to study the health effects on the service members deployed in the 1990–1991 Persian Gulf War. From Fiscal Year (FY) 1994 to FY 2005, the GWVIRP was managed by the US Army Medical Research and Materiel Command (USAMRMC) Military Operational Medicine Research Program (MOMRP). Research pertaining to GWI also has been funded intermittently through the Congressionally Directed Medical Research Programs’ (CDMRP) Peer Reviewed Medical Research Program (PRMRP) that supports selected military health-related research topics each fiscal year.
The MOMRP shared management responsibility for the GWVIRP with the CDMRP in FY 06 with separate $5 million (M) appropriations. Although the GWVIRP, renamed the Gulf War Illness Research Program (GWIRP), did not receive funding in FY 2007, a $10M appropriation renewed the program in FY 2008 to be managed fully by the CDMRP. Since that time, the GWIRP has been maintained with $8M appropriations in FY 2009, FY 2010, and FY 2011. The FY 2012 GWIRP appropriation was $10M. The program’s mission is to “Improve the health and lives of Veterans who have Gulf War Illness.” Thus, the program supports innovative, competitive peer-reviewed research for treatments that address the complexity of symptoms comprising GWI, identify objective markers (biomarkers) for the disease, and understand the pathobiology underlying GWI.
CDMRP GWIRP Processes
As with all CDMRP-managed programs, the GWIRP program management cycle includes a two-tier review process for application evaluation recommended by the National Academy of Sciences’ Institute of Medicine. The first tier of evaluation is an external scientific peer review of applications against established criteria for determining scientific merit. This review is conducted by scientific and clinician experts in Gulf War Illness with input from consumers - veterans suffering from GWI.
The second tier is a programmatic review conducted by an Integration Panel (IP) composed of program-specific researchers, clinicians, and consumers who evaluate applications on innovation, potential impact, programmatic priorities, and mechanism specific criteria. The IP is composed of prominent members of the GWI research community, including Gulf War consumers. The IP coordinates with the Office of Research and Development within the Department of Veterans Affairs (VA) to ensure there is no overlap of funding and that portfolios are complementary.
The IP recommends applications for funding that best fulfill the program’s vision and mission while also demonstrating innovative science. The recommendations of IP members enable the GWIRP to find and fund cutting-edge research and set important program priorities to benefit ill Gulf War Veterans. The Commanding General of USAMRMC issues final approval for funding prior to award negotiations and execution.
The Role of Veterans as Consumers
A unique aspect of the CDMRP is the active participation of consumer advocates throughout the program. Consumers for the GWIRP are Gulf War Veterans who are experiencing symptoms and illnesses related to their military service in the 1990-1991 Persian Gulf War theater. Consumer advocates are a vital part of all CDMRP programs in that they express the collective views of survivors, patients, family members, and those affected by the disease. They sit side by side with research professionals on both peer and programmatic review panels, they vote as equal members of these panels, and their voices play a pivotal role in maintaining an appropriate focus within the program.
CDMRP GWIRP Portfolio
The GWIRP has focused on the development of treatments to address the myriad of symptoms that plague ill Gulf War Veterans. To that end, the GWIRP has offered Clinical Trial Awards (CTAs), Innovative Treatment Evaluation Awards (ITEAs), and Investigator-Initiated Research Awards (IIRAs) that support pilot studies and larger, more definitive clinical trials to investigate potential treatments for GWI.
To date, the GWIRP has funded 3 CTAs ($3.6M), 5 ITEAs ($3.1M), and 39 IIRAs ($29M). Of these, 13 awards are focused on developing treatments, 15 are pursuing biomarkers, 8 are examining symptoms, and 6 are investigating exposures, while others are conducting basic research related to Gulf War Illness. Examples of these funded awards include the following:
a. IIRAs: (1) Beatrice Golomb, M.D., Ph.D., University of California, San Diego recently completed a 3½-year study (FY 2006 IIRA) examining the benefits of daily coenzyme Q10 (Q10) in ill Gulf War Veterans. Q10 is naturally produced in the human body where it is involved in cellular energy production as a key antioxidant. But, levels of Q10 can be inadequate to meet needs when there is increased “oxidative stress” or impaired energy production. Dr. Golomb hypothesized that mitochondrial dysfunction, linked to cellular energy production, may contribute to symptoms of GWI and sought to assess whether Q10 conferred benefit to overall health and symptoms in GWI.
Initial analysis of the study results found that the 100 mg dose led to better self-rated health scores than the 300 mg treatment. More importantly, fatigue with exertion, which 54% (25) of subjects reported at baseline, demonstrated significant improvement with Q10 at 100 mg compared to placebo treatment. The benefit to fatigue with exertion is important because increased exercise tolerance is a bridge to many health benefits (e.g., mood, function, and cognitive performance) as well as quality of life benefits crucial to ill Gulf War Veterans.
These findings provide important preliminary information that could inform a larger trial of Q10 better powered to show benefit to global health in ill Gulf War Veterans.
(2) Dr. Ronald Bach at the VA Medical Center in Minneapolis (VAMC Minneapolis) is using a FY 2008 GWIRP IIRA to further develop findings from VA-funded studies that indicated that ill Gulf War Veterans may be in a hyper-coaguable state of unknown etiology . Earlier work showed strong correlations between the plasma concentrations of inflammation-related proteins and symptoms of GWI. Thus, he hypothesized that chronic inflammation is part of GWI pathophysiology.
Analyses determined that C-reactive protein (CRP) levels, a marker of systemic inflammation, were significantly higher in Gulf War Veterans with three symptoms (as defined in health surveys) versus asymptomatic veterans. Dr. Bach subsequently observed statistically significant linear correlations between CRP and a group of 18 plasma proteins. This set of pro-inflammatory potential GWI biomarkers has been labeled “The Gulf War Proteome”, though more in-depth analysis is pending.
b. ITEAs: (1) Dr. Ashok Tuteja of the Western Institute for Biomedical Research, is using a FY 2009 ITEA to study irritable bowel syndrome (IBS) resulting from gastroenteritis commonly found in ill Gulf War Veterans. Dr. Tuteja is examining the potential of pro-biotic treatment (live bacteria that re-establish normal gut flora) to improve GWI-associated IBS, fatigue, joint pain, and headaches in a clinical trial of 80 Gulf War Veterans. This study is on-going.
(2) Dr. David Rabago of the University of Wisconsin, Madison, is using a FY 2010 ITEA to examine the effectiveness of routine nasal care plus saline or xylitol nasal irrigation compared to routine care alone as therapy for chronic rhino sinusitis and fatigue in 75 ill Gulf War Veterans. Study outcomes will gauge responses to surveys and assess the cost-effectiveness of the treatment. Dr. Rabago will also examine pro-inflammatory cytokine markers and cell types in the mucosal profile to elucidate biomarkers of the condition. This study is on-going.
The Way Forward
Since its inception at CDMRP in FY 2006, the GWIRP has served as a spring-board for GWI Research, identifying and developing a community of researchers and clinicians dedicated to pursuing robust research. The quality of applications submitted to the GWIRP has increased from overall scientific merit scores averaging 3.0 (on a scale of 1.0 to 5.0, with 1.0 representing a ‘perfect’ application) in FY 2006, to scores of 1.9 on average in FY 12. While quality has improved significantly, the quantity of awards made has not, given the available appropriations. In FY 2012, the GWIRP funded 13% of applications.
In FY 2010, the GWIRP took a bold step by offering a Consortium Development Award (CDA). This award provided $200,000 over one year for researchers to create a Coordinating Center and to establish the necessary collaborations at potential research sites to develop a multi-institutional GWI research effort.
The CDA supported experts from differing fields of GWI, and helped to bring their consolidated efforts to bear toward moving research forward, finding new treatments, developing biomarkers, and improving our understanding of GWI. Three CDAs were awarded, all of which scored very high on scientific merit, and also addressed a different focus of GWI.
In FY 2012, these three CDA awardees competed for a full Consortium Award. Two of the three were selected for initial funding (~$2.5M each), with the additional funds (again, ~$2.5M each) to be awarded as an option from FY 2014 funds, depending on the availability of funds and the progress of each consortium toward accomplishing its specific goals. While both of these awards are under negotiations, they are poised to propel the field of GWI research beyond what could be accomplished by individual researchers’ efforts.
In addition to the Consortium Award, in FY 2012 the GWIRP again offered the Investigator-Initiated Research Award, Clinical Trial Award, and the Innovative Treatment Evaluation Award established in FY 2009. These awards will add to the growing portfolio of GWIRP-funded, high-impact research designed to help our ill Gulf War Veterans.